EP3303312B1 - Verfahren zur herstellung von (e)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)-methanon-o-methyloxim - Google Patents
Verfahren zur herstellung von (e)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)-methanon-o-methyloxim Download PDFInfo
- Publication number
- EP3303312B1 EP3303312B1 EP16753456.9A EP16753456A EP3303312B1 EP 3303312 B1 EP3303312 B1 EP 3303312B1 EP 16753456 A EP16753456 A EP 16753456A EP 3303312 B1 EP3303312 B1 EP 3303312B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- benzofuran
- dione
- methanone
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- MCYLBKWHWSBJCZ-UHFFFAOYSA-O (2-hydroxyphenyl)methanone Chemical compound OC1=CC=CC=C1[C+]=O MCYLBKWHWSBJCZ-UHFFFAOYSA-O 0.000 title 1
- NGTOQTNVQSGXIS-BENRWUELSA-N 2-[(Z)-C-(5,6-dihydro-1,4,2-dioxazin-3-yl)-N-methoxycarbonimidoyl]phenol Chemical compound C=1C=CC=C(O)C=1C(=N/OC)/C1=NOCCO1 NGTOQTNVQSGXIS-BENRWUELSA-N 0.000 claims description 88
- 239000002904 solvent Substances 0.000 claims description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 29
- -1 5,6-dihydro-1,4,2-dioxazin-3-yl Chemical group 0.000 claims description 26
- 239000005784 Fluoxastrobin Substances 0.000 claims description 24
- UFEODZBUAFNAEU-NLRVBDNBSA-N fluoxastrobin Chemical compound C=1C=CC=C(OC=2C(=C(OC=3C(=CC=CC=3)Cl)N=CN=2)F)C=1C(=N/OC)\C1=NOCCO1 UFEODZBUAFNAEU-NLRVBDNBSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- RKNNOQIDQDTNSB-UHFFFAOYSA-N n-methoxy-1-benzofuran-3-imine Chemical compound C1=CC=C2C(=NOC)COC2=C1 RKNNOQIDQDTNSB-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 13
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 10
- 150000004703 alkoxides Chemical class 0.000 claims description 10
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 10
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 10
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 10
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 claims description 8
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 150000002576 ketones Chemical group 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 10
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XCBLZAJCKKRBED-UHFFFAOYSA-N 1-benzofuran-3-yl acetate Chemical compound C1=CC=C2C(OC(=O)C)=COC2=C1 XCBLZAJCKKRBED-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- JLLXSRLEXBECPY-UHFFFAOYSA-N 2-(carboxymethoxy)benzoic acid Chemical compound OC(=O)COC1=CC=CC=C1C(O)=O JLLXSRLEXBECPY-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- XURJYWPXVPKIOX-UHFFFAOYSA-N methyl 2-(2-ethoxy-2-oxoethoxy)benzoate Chemical compound CCOC(=O)COC1=CC=CC=C1C(=O)OC XURJYWPXVPKIOX-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- MGKPCLNUSDGXGT-UHFFFAOYSA-N 1-benzofuran-3-one Chemical compound C1=CC=C2C(=O)COC2=C1 MGKPCLNUSDGXGT-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RGBIKVOIODUDLX-UHFFFAOYSA-N 4-chloro-6-(2-chlorophenoxy)-5-fluoropyrimidine Chemical compound FC1=C(Cl)N=CN=C1OC1=CC=CC=C1Cl RGBIKVOIODUDLX-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 4
- WLWCQKMQYZFTDR-UHFFFAOYSA-N diethyl 2-chloropropanedioate Chemical compound CCOC(=O)C(Cl)C(=O)OCC WLWCQKMQYZFTDR-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 3
- DGMIGAHDDPJOPN-UHFFFAOYSA-N 4,6-dichloro-5-fluoropyrimidine Chemical compound FC1=C(Cl)N=CN=C1Cl DGMIGAHDDPJOPN-UHFFFAOYSA-N 0.000 description 3
- XGSFAIWGUAFXSG-UHFFFAOYSA-N 5-fluoro-4-hydroxy-1h-pyrimidin-6-one Chemical compound OC=1N=CNC(=O)C=1F XGSFAIWGUAFXSG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- GOWQBFVDZPZZFA-UHFFFAOYSA-N diethyl 2-fluoropropanedioate Chemical compound CCOC(=O)C(F)C(=O)OCC GOWQBFVDZPZZFA-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000002923 oximes Chemical group 0.000 description 2
- 235000020232 peanut Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- NXRGKFVQYZGDIY-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1.CC1=CC=CC(C)=N1 NXRGKFVQYZGDIY-UHFFFAOYSA-N 0.000 description 1
- XZDPPXQRJVSKTK-UHFFFAOYSA-N 2-(2-ethoxy-2-oxoethoxy)benzoic acid Chemical compound CCOC(=O)COC1=CC=CC=C1C(O)=O XZDPPXQRJVSKTK-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- AIMREYQYBFBEGQ-UHFFFAOYSA-N 2-methyl-2-nitropropane Chemical compound CC(C)(C)[N+]([O-])=O AIMREYQYBFBEGQ-UHFFFAOYSA-N 0.000 description 1
- NMWDYLYNWRFEMR-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1.CC1=CC=CC=N1 NMWDYLYNWRFEMR-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N Ethyl salicylate Chemical compound CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- ZIXLDMFVRPABBX-UHFFFAOYSA-N alpha-methylcyclopentanone Natural products CC1CCCC1=O ZIXLDMFVRPABBX-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 150000005125 dioxazines Chemical class 0.000 description 1
- 229940005667 ethyl salicylate Drugs 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 description 1
- 229910000026 rubidium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/01—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having one nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present disclosure provides an improved process of preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime, an intermediate useful for the synthesis of fluoxastrobin.
- Fluoxastrobin is a strobilurin-type fungicidal active ingredient used for controlling fungal diseases such as early blight, late blight, leaf spots, leaf rust, and Rhizoctonia solani. Fluoxastrobin has been registered for foliar use on peanuts, tuberous and corm vegetables, leaf petiole vegetables, fruiting vegetables, and turf, as well as seed treatment for potato, peanuts, and turf. Turf applications are labeled for professional pest control operators.
- Bayer provides a number of synthetic pathways to fluoxastrobin, although all proceed through a consecutive reaction of 4,6-dichloro-5-fluoro-pyrimidine with 2-chlorophenol and (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (4) as described in US 6,734,304 and shown below:
- EP0846691 describes a process for preparing 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines, which are known as intermediates for preparing compounds having fungicidal properties.
- EP0846691 also describes 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines compounds themselves, to intermediates for their preparation, and to processes for preparing the intermediates.
- WO2015/006203 describes a process for preparing fluoxastrobin, including (i) reacting benzofuran-3( 2H )-one O-methyl oxime with an alkyl nitrite in the presence of an acid to form (3 E )-2,3-benzofuran-dione O 3 -methyl dioxime; (ii) reacting (3 E )-2,3-benzofuran-dione O 3 -methyl dioxime with 2-haloethanol to form (3 E )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime; (iii) reacting (3 E )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl
- ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is an important intermediate in the synthesis of fluoxastrobin.
- known methods of synthesis of ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O- methyl oxime are low yielding, include toxic reagents, and require lengthy and tedious work-up techniques and procedures, such as recrystallization and chromatography, which increase fluoxastrobin industrial production costs.
- the present disclosure provides a process of preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime by:
- the disclosure includes a process for preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (1):
- the initial step in the disclosed process is the reacting of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite in the presence of a metal alkoxide to form (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2) as the predominant isomer.
- this reaction can be carried out by a number of nitrite reagents known in the art.
- n-butyl nitrite CH 3 (CH 2 ) 3 NO 2 and tert-butyl nitrite (CH 3 ) 3 CNO 2 are particularly useful for effecting the desired transformation.
- These reagents provide superior selectivity and better yields of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) compared to other nitrites.
- n-butyl nitrite and tert-butyl nitrite are substantially less toxic than many other alkyl nitrites (for example, methyl nitrite CH 3 NO 2 ).
- n-butyl nitrite or tert-butyl nitrite can be safely used when it is desired to selectively prepare (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) from benzofuran-3(2 H )-one O -methyl oxime (1) on a large scale in a synthesis lab or an industrial setting.
- the reaction of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite is carried out in the presence of an aprotic bipolar solvent, selected from N,N-dimethylformamide (“DMF”), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), or a combination thereof.
- an aprotic bipolar solvent selected from N,N-dimethylformamide (“DMF”), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), or a combination thereof.
- the reaction can be carried out by using N,N-dimethylformamide (“DMF").
- the reaction of benzofuran-3(2 H )-one O -methyl oxime (1) with at least one nitrite selected from n-butyl nitrite and tert-butyl nitrite is carried out in the presence of a metal alkoxide.
- the metal alkoxide can be lithium alkoxide, sodium alkoxide, potassium alkoxide, rubidium alkoxide, cesium alkoxide or a combination thereof, but is not limited thereto.
- the metal alkoxide can be sodium alkoxide, potassium alkoxide, or a combination thereof.
- Non-limiting examples of the sodium alkoxide include sodium methoxide (NaOCH 3 ) and sodium ethoxide (NaOCH 2 CH 3 ).
- Non-limiting examples of the potassium alkoxide include potassium tert-butoxide (KOC(CH 3 ) 3 ).
- the reaction typically starts by mixing a solution containing a nitrite reagent and metal alkoxide in a solvent with a solution of benzofuran-3(2 H )-one O -methyl oxime (1).
- the mixing can take place at a temperature in a range of about 0°C to about 25°C, for example, about 0°C to about 5°C.
- the reaction mixture is stirred at a temperature in a range of about 10°C to about 50 °C, for example, about 25°C to complete the reaction.
- the reaction When the reaction is carried out in the presence of n-butyl nitrite or tert-butyl nitrite the reaction produces one mole of n-butanol or tert-butanol for each mole of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2).
- the pH of the reaction mixture is adjusted by an acid (for example, by sulfuric acid or hydrochloric acid), and the precipitated product is filtered.
- the filtered product is washed with water to remove residual n-butanol or tert-butanol, unreacted metal alkoxide, impurities, and DMF.
- the product is then dried to remove residual water to give (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) as a solid.
- the next step in the disclosed process is the reaction of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3).
- the reagent 2-haloethanol may include 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, or a combination thereof.
- the 2-haloethanol may be 2-chloroethanol.
- ethylene oxide can be used instead of 2-haloethanol in the reaction.
- 2-haloethanol is less toxic than ethylene oxide (which is a gas at ambient temperature) and can be easily manipulated on a large scale.
- the reaction of (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) is conducted in the presence of a solvent.
- a solvent Any solvent suitable to carry out the reaction can be used.
- an aprotic bipolar solvent such as N,N-dimethylformamide (“DMF"), dimethylsulfoxide (“DMSO”), or N-methyl-2-pyrollidone (“NMP”), but is not limited thereto is used.
- the reaction can be carried out using N,N-dimethylformamide (“DMF").
- the reaction of (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2) with 2-haloethanol to form (2Z,3Z)-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) can be conducted in the presence of a base.
- the base can be a metal carbonate, for example, lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), cesium carbonate (Cs 2 CO 3 ), but is not limited thereto.
- the base can be potassium carbonate (K 2 CO 3 ).
- the reaction produces one mole of potassium bicarbonate (KHCO 3 ) for each mole of the (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) formed.
- the reaction is typically initiated by mixing (2 Z ,3 Z )-2,3-benzofuran-dione O 3 -methyl dioxime (2), 2-haloethanol, and the base in the solvent at a temperature in a range of about 0°C to about 35°C, for example, about 20°C to about 30°C.
- the reaction mixture can then be agitated at the temperature of reagent mixing to complete the reaction.
- the reaction mixture is usually heated at a temperature in a range of about 50°C to about 100°C, for example, about 75°C to about 80°C.
- the reaction is typically quenched with water to precipitate the product from the solution.
- the product is then collected by filtration and washed with water to remove solvent (such as DMSO), salt (such as potassium bicarbonate), unreacted 2-haloethanol, and unreacted base (such as potassium carbonate).
- solvent such as DMSO
- salt such as potassium bicarbonate
- unreacted 2-haloethanol such as potassium carbonate
- unreacted base such as potassium carbonate
- the next step in the disclosed process is the reaction of (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) with an acid to form ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4):
- the reaction can be carried out with hydrogen chloride (for example, hydrogen chloride gas), hydrogen bromide, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or acetic acid.
- hydrogen chloride for example, hydrogen chloride gas
- hydrogen bromide sulfuric acid
- methanesulfonic acid trifluoromethanesulfonic acid
- trifluoroacetic acid trifluoroacetic acid
- acetic acid By using acid as a catalyst, ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is prepared in high isomeric purity and excellent yield.
- the ratio of ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime to ( Z )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime may be greater than 85:1, 90:1, 92:1, 95:1, 98:1, or 99:1.
- the reaction of (2Z,3Z)-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) to ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is carried out in a solvent, which can be any solvent, stable to the action of an acid.
- the reaction can be carried out in the presence of an ester solvent, such as ethyl acetate, propyl acetate, butyl acetate, but is not limited thereto.
- the reaction can be carried out in the presence of butyl acetate.
- the reaction typically starts by contacting a solution of (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) with an acid at a temperature in a range of about 0°C to about 25°C, for example, about 0°C to about 15°C and maintaining that temperature for a period of about 1 hour to about 24 hours, for example, about 4 hours to about 6 hours until (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3) is consumed.
- the mixture is typically diluted with water and the pH of the aqueous solution is adjusted to pH > 12 with a base, for example, sodium hydroxide.
- a base for example, sodium hydroxide.
- the organic impurities are then removed by extraction with a solvent.
- the solvent used for the reaction can also be used for extraction.
- the pH of the aqueous phase is lowered with an acid, for example, with acetic acid to crystallize ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
- the product is then collected by filtration and washed with water to remove salts and impurities.
- a distinguishing feature of the instantly disclosed process is that isolation of (2Z,3Z)-2,3-benzofuran-dione O 3 -methyl dioxime (2), (2 Z ,3 Z )-benzofuran-2,3-dione O 2 -(2-hydroxyethyl) O 3 -methyl dioxime (3), and ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) is implemented by using simple filtration and does not require expensive, laborious, and time-consuming purification methods, such as recrystallization or chromatography.
- benzofuran-3(2 H )-one O -methyl oxime (1) Methods of synthesis of benzofuran-3(2 H )-one O -methyl oxime (1) are known in the art.
- benzofuran-3(2 H )-one O -methyl oxime (1) can be prepared as illustrated in Scheme 1.
- methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (7).
- Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (7) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (8) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (9) which is converted to benzofuran-3(2 H )-one (10) by methanolysis.
- Treatment of benzofuran-3(2 H )-one (9) with O -methylhydroxylamine and sodium acetate affords benzofuran-3(2 H )-one O -methyl oxime (1).
- the disclosed process for preparing ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) further comprises methods of preparing fluoxastrobin from the ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
- the disclosure includes a method for preparing fluoxastrobin comprising: (iv) reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4), optionally in the presence of a first solvent and optionally in the presence of a base, to form a ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6):
- the step of reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein each X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) may be carried out in the presence of a tertiary amine, for example, 1,4-diazabicyclo[2.2.2]octane (“DABCO”), 1,5-diazabicyclo[4.3.0]non-5-ene (“DBN”), or 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), and for example, 1,4-diazabicyclo[2.2.2]octane (“DABCO").
- DABCO 1,4-diazabicyclo[2.2.2]octane
- DBU 1,8-diazabicyclo[5.4.0]undec-7-
- an amount of 1,4-diazabicyclo[2.2.2]octane may be from about 0.02 moles to about 0.4 moles per mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (4).
- the amount of 1,4-diazabicyclo[2.2.2]octane is from about 0.02 moles to about 0.2 moles per mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (4).
- Step (iv) is followed by reacting the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6) with 2-chlorophenol, optionally in the presence of a second solvent and optionally in the presence of a base, to form fluoxastrobin:
- the first and second solvent may be the same or different.
- Steps (iv) and (v) in the process for preparing fluoxastrobin may be carried out as a one-pot process, i.e. without isolation and purification of intermediate (6).
- steps (iv) and (v) are carried out as a one-pot process, the first and second solvents are necessarily the same.
- an amount of the 4,6-di-halo-5-fluoro-pyrimidine (5) may be from about 1 mole to about 4 moles per one mole of the ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4).
- an amount of 2-chlorophenol may be from about 0.8 moles to about 4 moles per one mole of the ( E )-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O -methyl oxime (6).
- the step of reacting a 4,6-di-halo-5-fluoro-pyrimidine (5), wherein X 1 is halogen, with ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (6) may be carried out at a temperature of about 0°C to about 100 °C, for example, about 40°C to about 80°C.
- the reaction time may vary from about 1 hour to about 10 hours, for example, from about 1 hour to about 6 hours.
- fluoxastrobin may be prepared from ( E )-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O -methyl oxime (4) by
- the solvent in steps (iv) and (v) for either method for preparing fluoxastrobin can be a ketone solvent, for example, methyl iso-butyl ketone (MIBK).
- the base in steps (iv) and (v) of either method can be a metal carbonate, for example, potassium carbonate.
- X 1 may be fluorine, chlorine, bromine, and iodine.
- X 1 may be chlorine.
- Steps (iv) and (v) of the process of either method for preparing fluoxastrobin may be carried out in the presence of a solvent.
- the solvent may include a hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an amide solvent, an ester solvent, a sulfoxide solvent, a sulfone solvent, water, or a combination thereof.
- the hydrocarbon solvent may include an aliphatic solvent, an alicyclic solvent, an aromatic solvent, or a combination thereof.
- Non-limiting examples of the hydrocarbon solvent include petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, ethylbenzene, and cumene.
- Non-limiting examples of the halogenated solvent include chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and 1,1,2-trichloroethane.
- Non-limiting examples of the ether solvent include diethyl ether, diisopropyl ether, methyl-tert-butyl ether, methyl-tert-amyl ether, 1,4-dioxane, tetrahydrofuran ("THF”), 2-methyltetrahydrofuran, 1,2-dimethoxyethane (“DME”), and anisole.
- the ketone solvent include acetone, 2-butanone, methyl isobutyl ketone, cyclopentanone, and cyclohexanone.
- the ketone solvent may include methyl isobutyl ketone.
- Non-limiting examples of the nitrile solvent include acetonitrile ("ACN”), propionitrile, n-butyronitrile, iso-butyronitrile, and benzonitrile.
- Non-limiting examples of the amide solvent include N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DMA”), N-methylformamide, N-methylpyrrolidone (“NMP”), and hexamethylphosphoric triamide (“HMPA”).
- Non-limiting examples of the ester solvent include methyl acetate and ethyl acetate.
- Non-limiting example of the sulfoxide solvent include dimethyl sulfoxide (“DMSO”).
- Non-limiting example of the sulfone solvent include sulfolane.
- the solvent may be a mixture of the hydrocarbon solvent and the amide solvent.
- the solvent may be a mixture of the aromatic hydrocarbon solvent and the amide solvent.
- the aromatic hydrocarbon solvent in this mixture may include benzene, toluene, 1,2-xylene, 1,3-xylene, 1,4-xylene, ethylbenzene, and cumene.
- the amide solvent may include N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), and hexamethylphosphoric triamide (“HMPA”).
- the solvent may be a mixture of the aromatic hydrocarbon solvent such as any xylene or toluene and the amide solvent, which may be for example, N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
- the aromatic hydrocarbon solvent such as any xylene or toluene
- amide solvent which may be for example, N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
- DMF N,N-dimethylformamide
- DME N,N-dimethylacetamide
- NMP N-methylpyrrolidone
- HMPA hexamethylphosphoric triamide
- the solvent may be a mixture of the aromatic hydrocarbon solvent such as any xylene and the amide solvent, for example N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
- the solvent may be a mixture of the aromatic hydrocarbon solvent such as toluene and the amide solvent such as N,N-dimethylformamide (“DMF”), N,N-dimethylacetamide (“DME”), N-methylformamide, N-methylpyrrolidone (“NMP”), or hexamethylphosphoric triamide (“HMPA”).
- the base may include an inorganic base, an organic base, or a combination thereof.
- the inorganic base may include a hydroxide, a hydride, an acetate, a carbonate, a bicarbonate, or a combination thereof.
- Non-limiting examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
- Non-limiting examples of the organic base include trimethylamine, triethylamine, tributylamine, N,N-dimethylamine, N,N-di-iso-propylethylamine, N,N-dimethylbenzylamine, pyridine, 2-methylpyridine (2-picoline), 2,6-dimethylpyridine (2,6-lutidine), N-methylpiperidine, N-methylmorpholine (“NMM”), N,N-dimethylaminopyridine (“DMAP”), 1,5-diazobicyclo[4.3.0]non-5-ene (“DBN”), and 1,8-diazobicyclo[5.4.0]undec-7-ene (“DBU”).
- the product is dried by passing air at 20-30°C for 60 min, and subsequently air dried at 70-85°C until the moisture content is NMT 1.0% w/w to give 2-(carboxymethoxy)benzoic acid (8) (548 g, 85%) as a solid.
- IR (cm -1 ) 3060.43w, 1759.45s, 1577.24s, 1449.18s, 1361.45s, 1179.20s, 1090.38s, 890.75, 742.41.
- IR (cm -1 ) 3070.02, 2898.40, 1604.89s, 1398.80s, 1537.36, 1465.17, 1041.49, 985.45s, 747.70s, 628.55s, 554.54s.
- the mixture is warmed to 20-30°C, stirred for 4 h until the reaction is complete, and then cooled to 0-10°C.
- H 2 O (7,105 mL) is added very slowly at 0-10°C to quench the reaction.
- the pH of the mixture is adjusted to pH 1-2 using 50% aqueous H 2 SO 4 (665.76 g, 1.56 equiv.) while the temperature is maintained at 0-5°C.
- the mixture is then stirred at 5-10°C for 30 min.
- the pH of the reaction mixture is adjusted to pH >12 with an 11.13% solution of aqueous sodium hydroxide (2,461 g, 5.0 equiv.) while maintaining the temperature at 10-15°C.
- the reaction mixture is stirred for 15 min and the phases are separated.
- the product rich aqueous layer is washed with butyl acetate (2 ⁇ 1,470 mL) and the pH of the aqueous layer is adjusted to pH 5-5.5 using 50% aqueous acetic acid (323,5 g, 1.96 equiv.).
- the resultant mixture is cooled to 0°C and stirred for 30 minutes to crystallize the product.
- diethyl 2-chloromalonate may be performed by methods known in the art, for example by the method of Babu, G.R. et al. (Der Pharma Chemica (2011) 3(6):437-442 ).
- Sulfuryl chloride is added to diethyl malonate at 60°C.
- the molar ratio of sulfuryl chloride to diethyl malonate is approximately 1.2: 1.
- the generated HCl and SO 2 gases are vented to the scrubber as they are formed.
- the mixture is stirred for 6 h at 60°C and concentrated under reduced pressure to give diethyl 2-chloromalonate as a residue, which is carried forward without further purification.
- Diethyl 2-chloromalonate is added to the mixture of triethylammonium hydrofluoride and triethylamine at 80-90°C under stirring. A molar excess of triethylammonium hydrofluoride and triethylamine to diethyl 2-chloromalonateis used. The resulting mixture is stirred at 100°C for 18 hours. The mixture is cooled and diluted with water. The product is extracted with xylene. The phases are separated and the organic phase is concentrated to give diethyl 2-fluoromalonate as a residue, which is carried forward without further purification.
- a solution of diethyl 2-fluoromalonate in formamide is added to a solution containing a molar excess of sodium methylate in methanol heated at 65 °C for more than 4 hours.
- water is added.
- the mixture is acidified with hydrochloric acid to precipitate the product.
- the product is collected by filtration, washed with water and thoroughly dried to give 5-fluoropyrimidine-4,6-diol (75%) as a solid.
- 5-Fluoropyrimidine-4,6-diol is suspended in excess phosphorous oxychloride and the mixture is heated under stirring to 85°C for 4 hours until production of hydrogen chloride stops.
- phosphorous trichloride is added over 15 min followed by an equimolar charge of chlorine gas over 1-2 hours.
- the mixture is heated to 105-108°C and stirred until production of exhaust gases stops.
- the mixture is concentrated to a residue to remove excess POCl 3 at the pressure of 150-200 mbar.
- the residue is then distilled at 0.5 mbar pressure at approximately 40°C to give 4,6-dichloro-5-fluoropyrimidine (82%) as a liquid.
- MIBK methyl iso-butyl ketone
- DCFP 1,067 kg, 6.39 kmol
- 2-chlorophenol 825 kg, 1.003 equiv.
- water 4,4,000 L is added to the hot mixture to dissolve the formed salts.
- the lower salt phase is transferred to waste water pre-treatment by pressure hydrolysis.
- the remaining 4-chloro-6-(2-chlorophenoxy)-5-fluoropyrimidine (11) in MIBK is transferred to a storage tank for use in the final step.
- isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
- halogen refers to fluorine, chlorine, bromine, or iodine.
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Claims (17)
- Verfahren zum Herstellen von (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim, umfassend:(i) Umsetzen von Benzofuran-3(2H)-on-O-methyloxim (1) mit wenigstens einem Nitrit, ausgewählt aus n-Butylnitrit und tert-Butylnitrit, in der Gegenwart eines Metallalkoxids und eines aprotischen bipolaren Lösungsmittels, das N,N-Dimethylformamid, Dimethylsulfoxid, N-Methyl-2-pyrrolidon oder eine Kombination davon ist, um eine Zusammensetzung auszubilden, in der ein Isomer vorherrscht und (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2) das vorherrschende Isomer ist;(ii) Umsetzen des (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxims (2) mit 2-Haloethanol, um (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) auszubilden; und
- Verfahren nach Anspruch 1, das zusätzlich umfasst:
(iv) Umsetzen eines 4,6-Dihalo-5-fluor-pyrimidins (5), wobei X1 jeweils Halogen sind, mit (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4), um ein (E)-(2-((6-Halo-5-fluorpyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanon-O-methyloxim (6) auszubilden: - Verfahren nach Anspruch 1, wobei die Säure Chlorwasserstoff ist.
- Verfahren nach Anspruch 1, wobei das Metallalkoxid Natriumalkoxid, Kaliumalkoxid oder eine Kombination davon ist.
- Verfahren nach Anspruch 1, wobei (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) isoliert werden und
die Isolierung von (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) nicht die Rekristallisierung oder Chromatographie umfasst, und wobei die Reinheit des isolierten (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) 99 % oder mehr beträgt. - Verfahren nach Anspruch 1, wobei die Isolierung von (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2), (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) und (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) bei einer Temperatur von 0 °C oder höher stattfindet.
- Verfahren nach Anspruch 3, wobei Schritt (iv) in der Gegenwart einer Base und eines ersten Lösungsmittels durchgeführt wird; Schritt (v) in der Gegenwart einer Base und eines zweiten Lösungsmittels durchgeführt wird; und die Schritte (iv) bis (v) in einem Eintopfverfahren durchgeführt werden und das erste und das zweite Lösungsmittel dasselbe sind.
- Verfahren nach Anspruch 1, wobei die Umsetzung des (2Z,3Z)-2,3-Benzofuran-dion-O 3-methyldioxim (2) mit 2-Haloethanol in der Gegenwart eines aprotischen bipolaren Lösungsmittels erfolgt.
- Verfahren nach Anspruch 9, wobei das aprotische bipolare Lösungsmittel N,N-Dimethylformamid, Dimethylsulfoxid, N-Methyl-2-pyrrolidon oder eine Kombination davon ist.
- Verfahren nach Anspruch 1, wobei der Gehalt des (2Z,3Z)-2,3-Benzofurandion-O 3-methyldioxim (2) in einem Gemisch aus (3E)- und (3Z)-Isomeren 94 % bis 98 % beträgt.
- Verfahren nach Anspruch 1, wobei die Umsetzung des (2Z,3Z)-Benzofuran-2,3-dion-O 2-(2-hydroxyethyl)-O 3-methyldioxim (3) mit einer Säure in einem Esterlösungsmittel durchgeführt wird, wobei das Esterlösungsmittel n-Butylacetat ist.
- Verfahren nach Anspruch 2 oder Anspruch 13, wobei X1 Chlor ist.
- Verfahren nach Anspruch 2 oder nach Anspruch 14 in Abhängigkeit von Anspruch 2, wobei die Umsetzung des 4,6-Di-halo-5-fluor-pyrimidins (5) mit (E)-(5,6-Dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanon-O-methyloxim (4) in der Gegenwart eines tertiären Amins ausgeführt wird, das 1,4-Diazabicyclo[2.2.2]octan ist.
- Verfahren nach Anspruch 8 oder Verfahren nach einem der Ansprüche 13 und 14, wobei Schritt (v) in der Gegenwart eines Lösungsmittels und einer Base durchgeführt wird, wobei:das Lösungsmittel ein Ketonlösungsmittel ist; und/oderdie Base ein Metallcarbonat ist.
- Verfahren nach Anspruch 16, wobei:das Lösungsmittel Methylisobutylketon (MIBK) ist; und/oderdie Base Natriumcarbonat oder Kaliumcarbonat ist.
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- 2016-05-10 JP JP2017561838A patent/JP6930923B2/ja active Active
- 2016-05-10 CA CA2987545A patent/CA2987545C/en active Active
- 2016-05-10 RU RU2017146672A patent/RU2701862C2/ru active
- 2016-05-10 ES ES16753456T patent/ES2960228T3/es active Active
- 2016-05-10 WO PCT/IB2016/000871 patent/WO2016193822A1/en active Application Filing
- 2016-05-10 UA UAA201713048A patent/UA123210C2/uk unknown
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2017
- 2017-11-29 CO CONC2017/0012269A patent/CO2017012269A2/es unknown
Non-Patent Citations (1)
Title |
---|
AMIT KESHAV ET AL: "Reactive Extraction of Acrylic Acid Using Tri- n -butyl Phosphate in Different Diluents", JOURNAL OF CHEMICAL AND ENGINEERING DATA., vol. 54, no. 6, 11 June 2009 (2009-06-11), US, pages 1782 - 1786, XP055749161, ISSN: 0021-9568, DOI: 10.1021/je800856e * |
Also Published As
Publication number | Publication date |
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CO2017012269A2 (es) | 2018-02-20 |
RU2701862C2 (ru) | 2019-10-02 |
CA2987545C (en) | 2022-08-02 |
WO2016193822A1 (en) | 2016-12-08 |
RU2017146672A3 (de) | 2019-07-17 |
US20180148423A1 (en) | 2018-05-31 |
JP2018517696A (ja) | 2018-07-05 |
UA123210C2 (uk) | 2021-03-03 |
US10087152B2 (en) | 2018-10-02 |
MX2017015326A (es) | 2018-05-04 |
JP6930923B2 (ja) | 2021-09-01 |
RU2017146672A (ru) | 2019-07-01 |
ES2960228T3 (es) | 2024-03-01 |
CN107690428A (zh) | 2018-02-13 |
BR122019027818B1 (pt) | 2023-03-14 |
PL3303312T3 (pl) | 2024-06-17 |
CA2987545A1 (en) | 2016-12-08 |
EP3303312A1 (de) | 2018-04-11 |
BR112017025678A2 (pt) | 2018-08-07 |
BR112017025678B1 (pt) | 2021-12-28 |
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